t(14;14)(q11;q32) in biphenotypic blastic phase of chronic myeloid leukemia

A blastic crisis of chronic myeloid leukemia without a detectable chronic phase is reported. At diagnosis, blast cells present t(9;22)(q34;q11),t(14;14)(q11;q32) translocations and early B cell phenotype (DR +, TdT +, B4 +, BA1 +, J5 +). At relapse, the malignant clone evolves to a biphenotypic expression, the initial markers remain unchanged, and two myeloid antigens (My 7, My 9) appear. The wide overlap in percentages of blast cells displaying lymphoid and myeloid markers shows that a single clone bears antigens of both lineages. Simultaneous occurrence of a t(14;14)(q11;q32) translocation, usually found in T cell malignancies, and of a B cell phenotype raises the question of the relationship between chromosomal changes and surface marker expression. The malignant cell is assumed to be a progenitor cell, already committed to lymphoid lineage and retaining the potential to switch to myeloid lineage.     

Chronic myelogenous leukemia characterized by successive lymphoid and myelomonocytic blast crises

We report a 25 year-old male of CML, who repeated lymphoid blast crises twice and finally experienced a myelomonocytic blast crisis. In the first and the second crises, after 2 years of chronic phase, the blasts were only weakly positive or negative for terminal deoxynucleotidyl transferase. Based on other morphological features of the blasts, however, lymphoid blast crisis was strongly suspected. Actually, he responded well to the vincristine and prednisolone therapy. In the third crisis, the blasts showed myelomonocytic features. He did not respond to the same regimen, and died of intracranial infiltration during daunorubicin and cytosine arabinoside therapy after one year from the first crisis. Chromosomal analysis showed the karyotypes of 46, XY, t(9:22) (q34:q11) in the chronic phase, 45, XY, -7, -9, +der(9) t(7;9) (q11;p11), t(9:22) (q34:q11) in the lymphoid blast crisis, and 46, XY, t(9:22) (q34:q11), t(11:17) (q23:q25) in the myelomonocytic blast crisis.     

Mixed blast crisis with the cytogenetic evidence of three clonal evolutions

A 46-year-old man was diagnosed as having chronic myelogenous leukemia (CML) in chronic phase in Dec. 1985. In Dec. 1987, anemia and leukocytopenia progressed, and the percentage of blast cells increased in the bone marrow. The blast cells were lymphoblastoid and positive for TdT. It was treated as a lymphoid crisis with vincristine and prednisolone, and complete remission was achieved. However, the blasts (11%) were observed in the bone marrow in Mar. 1988, and the chromosomal analysis revealed 46, XY, t (2q-; 11q+), t (9q+; 22q-) in 13 out of 20 cells. In June, the percentage of the blasts increased again, but chromosomal analysis showed a different karyotype, 46, XY, t(2p-; 11p+), t(9q+; 22q-) which was observed in 9 out of 10 cells. Then, myeloblastoid cells increased rapidly in spite of the chemotherapy in Dec. 1988. The chromosomal analysis showed 46, XY, 2p-, 7q-, 9q+, 11p+, 22q- in all analyzed cells. The rearrangement of the bcr gene could be detected by the Southern blotting. The blasts were positive for CD7, CD11, CD13, CD33, CD36, CD41 and CD42, suggesting that the blasts had the surface phenotypes of both myeloid and megakaryocytoid-lineage. This is a case with the mixed blast crisis that changed from the lymphoid to the myelo-megakaryocytoid in nature, in which three clonal evolutions were observed during the clinical course.     

Differential diagnosis from isolated lymphoid extramedullary blast crisis from secondary non-Hodgkin lymphoma in chronic myelogenous leukemia: a case report and literature review

Case: Extramedullary blast crisis (EBC) is a special kind of blast crisis of chronic myelogenous leukemia (CML). It is more likely to be misdiagnosed as lymphoma when EBC cells are of lymphoid cell lineage and lymphadenopathy is the only symptom before the final diagnosis. In this study, we presented a patient with an unusual presentation of CML transformation as a rapid growth of generalized lymphadenopathy that appeared 5 months after the initial diagnosisof CML. The patient underwent the left supraclavicular lymph node biopsy and repeat bone marrow aspiration. The revealed CD3+, terminal deoxynucleotidyl transferase (TdT)+, CD5+, CD23+, myeloperoxidase (MPO)-, CD20-, cyclin D1-, CD10-, which was consistent with the diagnosis of T-cell lymphoblastic lymphoma (T-LBL). Fluorescence in situ hybridization (FISH) verified the BCR-ABL rearrangement, and T-cell EBC of CML was finally diagnosed. Our report suggested that the FISH was necessary to distinguish isolated lymphoid extramedullary blast crisis from secondary NHL in CML.     

Lymphoid blast crisis in a patient with Philadelphia-chromosome-negative chronic myelocytic leukemia

A 24-year-old man with Philadelphia-chromosome (Ph)-negative chronic myelocytic leukemia (CML) developed lymphoid blast crisis. In the chronic phase, karyotype was normal and the clinical and hematological features were indistinguishable from those of Ph-positive CML. Rearrangement of the breakpoint cluster region (bcr) was observed. In the blast phase, blast cells showed early B-cell phenotype (CALLA+, Ia+, TdT+) with a rearranged immunoglobulin heavy-chain gene joining region (JH). By using an immunoblotting method and antiphosphotyrosine sera, P210bcr-abl protein was detected. The patient responded well to vincristine and prednisolone (VP) therapy. These findings support the concept that Ph-negative bcr+ CML can behave in a very similar fashion to Ph-positive CML, not only in the clinical features of the chronic phase but also in the manner of the blast crisis.     

Adenosine deaminase and ecto-5''-nucleotidase activities in various leukemias with special reference to blast crisis: significance of ecto-5''-nucleotidase in lymphoid blast crisis of chronic myeloid leukemia

Adenosine deaminase (ADA) and ecto-5'-nucleotidase (5'-N) activities were examined in peripheral leukocytes from patients with leukemias, including nine patients with chronic myeloid leukemia (CML) in blast crisis. Four of none cases of CML in blast crisis were myeloid and the remaining lymphoid morphologically. The diagnosis of CML in lymphoid blast crisis was further contributed by the measurement of terminal deoxynucleotidyl transferase (TdT) activity. In all four cases of lymphoid blast crisis and one of myeloid blast crisis, leukemia cells had high 5'-N activity, while there was a little or no detectable activity in those from four cases of myeloid blast crisis and all of CML in chronic phase. ADA activity was high in seven of nine patients with blast crisis. Taken together, leukemia cells from two cases of lymphoid blast crisis had high ADA and 5'-N activities comparable to those in acute lymphocytic leukemia (ALL) cells. In contrast, the enzyme activities of leukemia cells from all but one patient in myeloid blast crisis were in a range similar to acute myeloid leukemia cells. The implications of these findings are as follows: (1) 5'-N may be used as a new biochemical marker of CML in lymphoid blast crisis. (2) Some lymphoid cells of CML in blast crisis have high ADA, 5'-N, and TdT activities and thus are very similar to ALL cells.     

The influence of time of storage,temperature of storage,platelet number in platelet-rich plasma,packed cell,mean platelet volume,hemoglobin concentration,age, and sex on platelet aggregation test

Loss of the p53 gene alleles was investigated in 26 patients with Ph+BCR/ABL+ chronic myeloid leukemia (CML) by means of the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis using the restriction enzymeAccII. In all cases, peripheral blood and/or bone marrow samples were obtained at different times during the chronic phase of the disease and at blast crisis, and in some of them also at the accelerated phase. Of the 12 cases considered informative, 11 evolved into myeloid type blast crisis and one into a lymphoid blast crisis, whereas only two showed an i(17q) chromosome at cytogenetic study. In four of the 12 informative cases, a loss of one p53 gene allele was observed, in all cases coincident with the development of the accelerated phase or blast crisis. One patient with a deleted p53 gene allele, in whom it was possible to analyze the gene structure in the three CML evolutive phases (chronic and accelerated phases and blast crisis), showed loss of the p53 gene allele in both the accelerated and the biastic phase, but not during the chronic phase. On the other hand, one of the two cases with an i(17q) chromosome exhibited one allelic deletion of the p53 gene. Thus, the relatively frequent monoallelic deletion of the p53 gene coincident with the appearance of the blast crisis registered in the present study would support a possible role of the p53 gene alterations in the evolution of CML to its final stages.     

Phenotypic and genotypic analysis of chronic myelogenous leukaemia with T lymphoblastic and megakaryoblastic mixed crisis

A case of blast crisis in chronic myelogeneous leukaemia (CML) in which two distinct cell lineages were involved is presented. The phenotype of blasts in lymph nodes was T11 (CD2)+, Ia+, TdT+, suggesting T cell lineage. On the other hand, blasts in bone marrow and peripheral blood expressed platelet glycoprotein IIb/IIIa complex on their surface, suggesting megakaryocyte lineage. Cytogenetic analysis of lymph node and bone marrow cells revealed the abnormalities, inv(7) (p15q34) and t(1;3) (q23;q21), respectively, as well as the presence of the Ph1 chromosome in both cell types. Rearrangement of the T cell receptor beta-chain gene was detected in lymph node blasts, although blast cells in peripheral blood showed a germ line configuration. The involvement of T cell and megakaryocyte lineages in the blast crisis phase of CML was confirmed in our phenotypic and genotypic analysis, and the pathogenic association between blast crisis lineages and the additional chromosome abnormalities present is discussed.     

Maturation of B-lineage blast crisis cells in chronic myeloid leukemia

A 44 year-old Chinese male presented with lymphoid blast crisis of chronic myeloid leukemia, in which the blast cells exhibited a pre-pre-B cell phenotype (B4+B1-J5+12+smIg-). There was a phenotypic transition during the course of the disease to a more mature B cell phenotype (B4+B1+J5+12+smIgG lambda+). The maturation of blast crisis cells may be related to the chemotherapeutic agents used in the treatment of the disease.     

Blast crisis of chronic myelogenous leukemia with blasts expressing both immature B lymphocyte- and myelomonocyte-associated antigens and differentiating into basophils in vitro

A 43-year-old woman with Ph1-positive chronic myelogenous leukemia (CML) was diagnosed as having blastic crisis. The phenotype of blasts was CD9+, CD10+, CD19+, CD11b+ and CD33+, suggesting the B Lymphoid and myeloid mixed lineage. Two color analysis of CD10 and CD33 revealed that 50% of blast cells had both B lymphocyte- and myelomonocyte-associated surface markers. Rearrangement of the immunoglobulin heavy chain gene was detected. After culturing blasts with 12-o-tetradecanoyl-phorbol 13 acetate (TPA), basophilic granules appeared in cytoplasm of the cells. These granules were positive for toluidine blue staining. This finding that the biphenotypic blasts expressing both B lymphoid and myelomonocytoid features differentiated into basophils suggests that blasts of this case are derived from a common progenitor of B lymphoid and myeloid lineages including basophil.     

Translocation (3;21) in Philadelphia chromosome-positive chronic myelogenous leukemia prior to the onset of blast crisis

Two female patients in the chronic phase of CML were found to have, in addition to t(9;22), a new karyotypic abnormality--t(3;21)(q26;q22)--present in bone marrow cells. At diagnosis, this abnormality was observed in a small number of marrow cells in both patients, and as the disease progressed in patient 1, the percentage of cells showing t(3;21) was increased, reaching 100% as the transformation to blast crisis occurred. These observations suggest that t(3;21) may represent a new and rare nonrandom rearrangement which may be identified prior to the onset of blast crisis.     

Separation of lymphoid and myeloid blasts in the mixed blast crisis of chronic myelogenous leukemia: no evidence for Ig gene rearrangement in CALLA-positive blasts

Recent studies suggest that lymphoid blast crisis cells of chronic myelogenous leukemia (CML) expressing the common acute lymphoblastic leukemia antigen (CALLA) are B precursor cells, based on the demonstration of immunoglobulin (Ig) gene rearrangement similar to common acute lymphocytic leukemia. There is little evidence to suggest whether the cells with similar lymphoid characteristics in the mixed blast crisis of CML are also committed to B cell lineage. A patient in "mixed" blast crisis of CML was studied. On the basis of morphology, cytochemistry, and immunological studies, the blasts were classified as having either lymphoid or myeloid characteristics. A proportion of the leukemic blasts expressed CALLA, whereas others expressed My7 antigen. In order to characterize both populations of cell further, CALLA+ blasts and My7+ (myeloid) blasts were isolated by fluorescence-activated cell sorting. The My7+ cells were highly proliferative in cell culture blast colony assays, retained the Ph1 chromosome, and were indistinguishable from acute myelogenous leukemia blasts. The CALLA+ cells were also Ph1-chromosome positive, but in contrast, were poorly proliferative in vitro. Of particular note was their retention of germline configuration of Ig genes, thus distinguishing them from blasts in the lymphoid crisis of CML. We conclude that the lymphoid component in mixed blast crisis may represent a stage of differentiation prior to commitment to B lineage.     

Dual rearrangement of immunoglobulin and T-cell receptor genes in blast crisis of CML

Dual rearrangement of immunoglobulin and T-cell antigen receptor (beta, delta) genes was demonstrated in a case of Philadelphia chromosome-positive chronic myeloid leukemia (CML) in blast crisis. The blast cells, showing L2 morphology and high activity of TdT, expressed pre-B cell (CD19+, Ia+) and myeloid (CD13+, CD34+) surface antigens but lacket T-cell antigens (CD2-, CD7-). Cytogenetic studies on bone marrow and peripheral blood revealed the Phl chromosome in all metaphases analyzed, majority of which also had the additional chromosome changes, +8, +10, +21. Furthermore, molecular analysis of the breakpoint cluster region (bcr) on chromosome 22 showed a rearrangement, confirming the CML origin of the blast cells.     

Emergence of a cell line with extreme hypodiploidy in blast crisis of chronic myelocytic leukemia.

Cytogenetic studies in a patient with chronic myelocytic leukemia (CML) demonstrated the emergence of an extremely hypodiploid cell line at the time of blast crisis, a modal chromosome number of 35, with the modal karyotype 35,XY, -3, -4, -5, -7, -9, -11, -12, -13, -15, -16, -17, -19, -20, -22, + t(9;22) (q34;q11, + Mar1, + Mar2, + Mar3. Giemsa-banding confirmed complex chromosome rearrangements and demonstrated distinct banding patterns for the marker chromosomes. Cytologic characteristics of the leukemia blasts were predominantly myeloid. There was no important clinical response to chemotherapy, including vincristine and prednisone, or to radiotherapy.     

Heterogeneous Blast Cell Crises in Philadelphia Negative Chronic Granulocytic Leukaemia

S ummary . A case of Philadelphia negative chronic granulocytic leukaemia (Ph^1- CGL) is described showing features only previously demonstrated in Ph¹⁺ disease. These features include: (1) lymphoid blast crisis, determined by morphology and immunological marker analysis; (2) dual blast cell populations that can be distinguished both morphologically and by immunological markers; (3) clonal evolution, as shown by the emergence of chromosome markers and in one of the cell lines a change in membrane phenotype. These changes were apparently associated with the emergence of a relatively drug resistant subclone of leukaemic cells. This study demonstrates that the lymphoid blast crisis of CGL, and its sequelae, can occur in Ph^1- cases. It is similar in respect to morphology, enzyme, and membrane markers and responsiveness to vincristine and prednisolone therapy to the lymphoid blast crisis seen in Ph¹⁺ CGL. This suggests that the Philadelphia chromosome is a clonal marker only, and its presence is not directly related to the subsequent clinical course of the disease.     

Transformation of bilineal hybrid acute leukemia to acute lymphoid leukemia: a case report with serial analyses of cytogenetics and gene rearrangement

A 17-year-old male with bilineal hybrid acute leukemia is described. Two-color flow cytometric analysis of blast surface phenotype revealed that there were two groups of blasts which showed either CD 10+ CD 19+ CD 13- CD 33- or CD 10- CD 19- CD 13+ CD 33+, but not both. He developed a complete remission by treatment with vincristine, prednisolone, adriamycin, and L-asparaginase. After 8 months, however, leukemia relapsed and lymphoid blasts were dominant. Cytogenetic analysis at presentation showed 46,XY,t(3;9)(p21;p22), and at relapse it showed 46,XY,t(1;3;9)(1pter----1q32::3p25----3pter;3 qter----3p21::9p22----9pter; 9qter----9p22::3p21----3p25::1q32----1q ter),t(2;19)(p21;q13). Analysis of the heavy chain joining region at diagnosis showed three hybridizing bands, all rearranged, but at relapse only one rearranged band. Analysis of the constant region for the beta T-cell receptor gene (TCR beta) both at diagnosis and at relapse showed one rearranged and one germline band, suggesting that rearrangement of one allele of TCR beta of not only lymphoid but also myeloid blasts occurred. It is considered that the target cell of lymphoid leukemia cells and that of myeloid leukemia cells at diagnosis were the same, which differentiated to two lineages, and the clone which evolved from lymphoid lineage proliferated at relapse.     

Secondary T-acute lymphoblastic leukaemia mimicking blast crisis in chronic myeloid leukaemia

A 34-year-old man with chronic myeloid leukaemia (CML) firstly developed a lymphoid blast crisis of B-cell type. After a second chronic phase which lasted for > 4 years with maintenance chemotherapy of hydroxyurea, 6-mercaptopurine and methotrexate, he developed a T-cell acute lymphoblastic leukaemia of TcR-gammadelta+ type. Cytogenetic analysis revealed disappearance of the t(9;22) translocation and appearance of new abnormalities consistent with the diagnosis secondary acute leukaemia. To our knowledge, secondary leukaemia in CML has not previously been reported.     

Chromosome banding studies in Philadelphia chromosome positive myeloid leukaemia.

A cytogenetic study of Ph1 positive myeloid leukaemia in both chronic and acute phases had been made by a chromosome banding technique. The translocation (t(9;22)(q34;q11), designated t(Ph1) was present in the myeloid cells of 43 of 44 patients; the exceptional case had normal number 9 chromosomes and a different translocation (t(19;22)(q13;q11)). A translocation additional to that involving the Ph1 was found as a stable abnormality present in all myeloid cells in 4 patients, chromosome 17 being involved in 2. The association of isochromosome number 17 with blast crisis was confirmed. New data were obtained concerning the significance of duplicated or dicentric Ph1 chromosomes and their relationship with the 9q+ anomaly. Monoclonal origin of Ph1 was confirmed in cases with polymorphic number 22 or 9 chromosomes.     

Treatment of chronic myeloid leukemia blast crisis with vindesine and prednisone

Sixteen patients in chronic myeloid leukemia blast crisis entered a phase II trial with vindesine and prednisone. Median duration of the chronic phase was 29 months in 13 patients, one previously had polycythemia vera, and two presented with a primary blast crisis. Eleven patients had myeloblastic features, as evidenced by morphology, cytochemistry, and cell surface antigens; three had a mixture of myeloid and lymphoid blast cells with lymphoblastic predominance; one had blast cells which displayed lymphoid characteristics; and one was classified as undifferentiated. Three patients had complete remissions lasting 1 month (myeloid), 3 months (mixed), and 5 months (lymphoid). Eleven patients had minor responses, with a median duration of 3 weeks (eight with myeloid, two with mixed, and one with undifferentiated). Two patients did not respond to vindesine. Leukopenia and thrombocytopenia were severe and prolonged independent of their morphologic or immunologic phenotype.